4-Substituted derivatives of pyrazolo [1,5-a]-quinoxaline-3-carboxylic acids and esters

ABSTRACT

New 4-substituted derivatives of pyrazolo[1,5-a]-quinoxaline-3-carboxylic acid, esters and their salts have the formula ##STR1## R 1  is hydrogen, lower alkyl or a salt forming ion; R 2  is hydrogen, lower alkyl, phenyl-lower alkylene or amino-lower alkylene; R 3  is hydrogen, lower alkyl, halogen or lower alkoxy; and X is oxygen or sulfur. 
     The new compounds are useful as anti-inflammatory agents.

This application is a continuation-in-part of application Ser. No.628,277, filed Nov. 3, 1975, U.S. Pat. No. 3,994,893, Nov. 30, 1976.

SUMMARY OF THE INVENTION

This invention relates to new 4-substituted derivatives of pyraxolo[1,5-a]quinoxaline-3-carboxylic acids and esters which have the formula##STR2## wherein R₁ is hydrogen or lower alkyl; R₂ is hydrogen, loweralkyl, phenyl-lower alkylene or an amino-lower alkylene group, i.e.,##STR3## wherein R₄ and R₅ each is hydrogen or lower alkyl or togetherwith the nitrogen complete an unsubstituted or substituted pyrrolidino,piperiodino, piperazinyl or morpholino group, the substituent on theheterocyclic being one or two lower alkyl groups; R₃ is hydrogen, loweralkyl, halogen or lower alkoxy; X is oxygen (--O--) or sulfur (--S--);and salts thereof.

The foregoing symbols have the same meaning throughout thisspecification.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that certain intermediates described in parentapplication Ser. No. 628,277, filed Nov. 3, 1975, now U.S. Pat. No.3,994,893 i.e., those compounds of formula I having a lower alkoxy groupin the 4-position, themselves have antiinflammatory effects as docertain new analogs thereof. This invention relates to those groups ofcompounds.

The various groups represented by the symbols are of the following kind:

The lower alkyl groups are straight or branched chain hydrocarbon groupshaving up to seven carbon atoms in the chain, e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl, etc.The C₁ -C₄ lower alkyl groups and expecially C₁ -C₂ groups arepreferred.

The phenyl-lower alkylene groups have a phenyl group attached to analkyl chain such as those described. The same carbon preferences applyespecially to phenylmethyl and phenylethyl.

The halogens are the four common halogens, but chlorine and bromine arepreferred, especially the first.

The amino-lower alkylene groups referred to above are preferably linkedto the ring through an oxygen atom, e.g., X is oxygen. They have thegroup ##STR4## attached to an alkylene chain like those described abovewith the C₂ -C₄ and C₂ -C₃ alkylene chains constituting preferred andespecially preferred groups, respectively. R₄ and R₅ each is hydrogen orlower alkyl or together with the nitrogen complete an unsubstituted orsubstituted heterocyclic of the group pyrrolidine, piperidine,piperazine or morpholine, each of which may bear one or two methylgroups. Such amino-lower alkylene groups include, for example,aminoethyl, aminopropyl, methylaminoethyl, methylaminopropyl,ethylaminoethyl, propylaminoethyl, isopropylaminoethyl,dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl,dipropylaminoethyl, methylethylaminoethyl, piperidinomethyl,piperidinoethyl, pyrrolidinomethyl, pyrrolidinoethyl,piperazin-1-ylmethyl, 2-piperazine-1-ylethyl, morpholinomethyl,2-morpholinoethyl, 4-methylpiperazine-1-ylmethyl,4-hydroxyethylpiperazine-1-ylmethyl, 4-methylpiperidinomethyl, etc.

The products of the examples are preferred embodiments.

Especially preferred compounds of formula I are those wherein

R₁ is lower alkyl, especially ethyl;

R₂ is hydrogen or lower alkyl, especially hydrogen, methyl or ethyl;

R₃ is hydrogen or lower alkyl, especially hydrogen;

X is oxygen or sulfur, especially oxygen.

The compounds of formula I are produced from a 2-nitrophenylhydrazine ofthe formula ##STR5## (produced by the method described in U.S. Pat. No.3,369,897, Feb. 20, 1968) which is made to react with analkoxymethyleneoxalacetic acid ester of the formula ##STR6## wherein Rand R₁ each is lower alkyl, preferably ethyl, e.g., by heating at atemperature about reflux temperature in glacial acetic acid. Theresulting compound of the formula ##STR7## is hydrogenated in thepresence of catalyst like palladium on carbon in glacial acetic acid oran alcohol like ethanol or butanol, producing a compound of the formula##STR8## (or its keto form).

The intermediate of formula V is halogenated with a halogenating agent,e.g., a phosphorus oxyhalide like phosphorus oxychloride to produce acompound of the formula ##STR9## wherein X is halogen (preferablychlorine or bromine).

The compound of formula VI is then treated with a compound of theformula

    R.sub.2 XH                                                 (VII)

preferably a metal salt thereof like an alkali metal or alkaline earthmetal salt. Such reactants include, for example an alkali metal alkoxidelike sodium methoxide, potassium ethoxide or the like or an alkali metalsalt of a mercptan like the sodium salt of methyl mercptan, etc. Thereaction is effected by heating in an inert solvent to obtain thedesired product of formula I.

The ester is converted to the acid (R₁ ═H) by hydrolysis, e.g., with anequivalent of base like sodium or potassium hydroxide in an alcohol likeethanol.

Basic compounds of formula I, e.g., those having an amino-lower alkylenegroup, form salts which are also part of this invention. The saltsinclude acid addition salts, particularly the non-toxic, physiologicallyacceptable members. These salts are formed by reaction with one or moreequivalents of any of a variety or inorganic and organic acids,especially the strong acids, providing acid addition salts including,for example, hydrohalides (especially hydrochloride and hydrobromide),sulfate, nitrate, borate, phosphate, oxalate, tartrate, maleate,citrate, acetate, ascorbate, succinate or aryl- or alkanesulfonates likebenzenesulfonate, methanesulfonate, cyclohexanesulfamate andtoluenesulfonate. The acid additon salts frequently provide a convenientmeans for isolating the product, e.g., by forming and precipitating asalt (which is not necessarily non-toxic) in an appropriate medium inwhich the salt is insoluble, then after separation of the salt,neutralizing with an equivalent of base such as barium hydroxide orsodium hydroxide, to obtain the free base of formula I. Other salts canbe formed from the free base by reaction with one or more equivalents ofacid containing the desired anion.

Certain members, i.e., wherein R₁ is hydrogen, form salts with metals,e.g., alkali metals like sodium, alkaline earth metals like calcium andmagnesium, etc., e.g., by treating an ester, i.e., R₁ is lower alkyl,with an excess of base. These preferred salts are useful to form solublederivatives or as intermediates. They are also within the scope of theinvention.

Additional experimental details are found in the examples.

The new compounds of this invention have antiinflammatory properties andare useful for administration orally or parenterally as antiinflammatoryagents, for example, to reduce local inflammatory conditions such asthose of an edematous nature or resulting from proliferation ofconnective tissue in various mammalian species such as rats, dogs andthe like when given orally or parenterally in dosages of about 5 to 50mg/kg/day, preferably 5 to 25 mg/kg/day, in single or 2 to 4 divideddoses, as indicated by the carageenan edema assay in rats or delayedhypersensitivity skin reaction test.

The compounds of the invention can be utilized by formulating incompositions such as tablets, capsules or elixirs for oraladministration or in sterile solutions or suspensions for parenteraladministration. About 10 to 250 mg. of a compound or mixture ofcompounds of formula I or physioligically acceptable salt (preferablyacid addition salt) is compounded with physiologically acceptablevehicle, carrier, excipient, binder, preservative, stabilizer, flavor,etc., in a unit dosage form as called for by accepted pharmaceuticalpractice. The amount of active substance in these compositions orpreparations is such that a suitable dosage in the range indicated isobtained.

The compounds of this invention can also be applied topically asantiinflammatory agents formulated in a conventional lotion, ointment,or cream containing about 0.1 to 3 percent by weight of a compound offormula I or its salt.

The following examples are illustrative of the invention and constitutepreferred embodiments. They also serve as models for the preparation ofother members of the group which can be produced by suitablesubstitution of starting materials. All temperatures are in degreescelsuis.

EXAMPLE 1 a. 1-(2-Nitrophenyl)-1H-pyrazole-4,5-dicarboxylic acid,diethyl ester

5 g. of 2-nitrophenylhydrazine are dissolved in 50 ml. of glacial aceticacid and 7.9 g. of ethoxymethyleneoxalacetic acid ethyl ester in 50 ml.of glacial acetic acid are slowly added dropwise. After the addition hasbeen completed, the reaction mixture is refluxed for at least 3 hours.After cooling, the solvent is distilled off first under water vacuum andthen under oil pump vacuum. The dark, oily residue is dissolved in 20ml. of tetrahydrofuran, 10 ml. of ether are added and the mixture iskept in the refrigerator for 24 hours. The product,1-(2-nitrophenyl)-1H-pyrazole-4,5-dicarboxylic acid, diethyl ester, isobtained in the form of large crystals, yield 11.5 g. The produce isrecrystallized from cyclohexane and obtained as yellow crystals; yield9.8 g., m.p. 45°-46°.

b. 4-Hydroxypyrazolo [1,5-a]quinoxaline-3-carboxylic acid, ethyl ester

50 g. of the product of part a are dissolved in 400 ml. of glacialacetic acid and hydrogenated at 65° in the presence of 0.2 g. ofpalladium on carbon. At the end of the hydrogen uptake, the mixture isfiltered, the solvent is distilled off and the residue is recrystallizedfrom dioxane containing activated carbon to obtain4-hydroxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester aswhite, matted needles; yield 28 g., m.p. 249°-251°.

EXAMPLE 2 4-Chloropyrazolo[1,5-a]quinozalline-3-carboxylic acid, ethylester

50 g. of the product of Example 1, part b in 200 ml. of phosphorusoxychloride are refluxed for three hours. After distilling off theexcess phosphorus oxychloride,4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl estercrystallizes. The distillation residue is stirred shortly with ice waterand then the crude product is filtered off. The crude produce is driedbriefly over potassium hydroxide and recrystallized from acetone. Thepure product is obtained as white needles; yield 39.5 g., m.p.105°-106°.

EXAMPLE 3 4-(Ethoxy)pyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethylester

a. 5.5 g. of 4-chloropyrazolo[1,5-a]quinozaline-3-carboxylic acid, ethylester is heated for two hours with 10 ml. of a 2 molar sodium ethylatesolution. The hot reaction solution is filtered and, upon cooling,4-ethoxypyrazolo[1,5-a]quinoxaline-3 -carboxylic acid, ethyl estercrystallizes in the form of white needles. The product is recrystallizedfrom ethanol to obtain 3.4 g. of white crystals, m.p. 88°-90°.

b. 4-Ethoxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid

To a solution of 2.85 g. of4-ethoxypyrazolo[1,5-a]-quinoxalline-3-carboxylic acid, ethyl ester inhot ethanol, there is added 10 ml. of 10% aqueous sodium hydroxide andthe mixture refluxed for 2 hours. The mixture is concentrated underreduced pressure and the residue dissolved in water. The solution isfiltered and neutralized with dilute hydrochloric acid. The precipitated4-ethoxypyrazolo[1,5-a]-quinoxaline-3-carboxylic acid is filtered andwashed with a small amount of cold water. The product is crystallizedfrom ethanol.

c. 4-Ethoxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid, sodium salt

2.57 g. of 4-ethoxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid isdissolved in 100 ml. of 0.1N aqueous sodium hydroxide, the solution isfiltered and lyophilized to give4-ethoxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid, sodium salt.

EXAMPLE 44-[3-Dimethylamino)propoxy]pyrazolo[1,5-a]quinoxaline-3-carboxylic acid,ethyl ester

A solution of 2.76 g. of4-chloropyrazolo[1,5-a]-quinoxaline-3-carboxylic acid, ethyl ester inbenzene is added dropwise, at 10° to a stirred solution of 1.03 g. of3-dimethylamino-1-propanol and 0.64 g. of butyl lithium in 30 ml. ofbenzene. The reaction mixture is heated under refllux for 3 hours and isthen filtered and concentrated under reduced pressure. The oily residueis dissolved in petroleum ether, treated with carbon and cooled for 12hours in the refrigerator. The product,4-[3-(dimethylamino)-propoxy]pyrazolo[1,5-a]quinoxaline-3-carboxylicacid, ethyl ester, crystallizes in the form of white needles, m.p.78°-81°.

EXAMPLE 5 4,5-Dihydro-4-thioxopyrazolo[1,5-a]quinoxaline-3-carboxylicacid, ethyl ester

8.28 g. of 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethylester are heated at 80° for 1 hour with 2.22 g. of NaHS.H₂ O and 20 ml.of dimethylformamide. On cooling, the product4,5-dihydro-4-thioxopyrazolo[1,5-a]-quinoxaline-3-carboxylic acid, ethylester crystallizes and it is recrystallized fromdimethylformamide-ethanol as yellow needles, m.p. 270-272°.

EXAMPLE 6 4-(Methylthio)pyrazolo[1,5-a]quinoxaline-3-carboxylic acid,ethyl ester

2.76 g. of 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid ethylester are heated with 0.71 g. of the sodium salt of methyl mercaptan indimethylformamide. After cooling, the reaction mixture is poured intowater. The product 4-(methylthio)pyrazolo[1,5-a]quinoxaline-3-carboxylicacid, ethyl ester is filtered under suction and crystallized fromethanol as white needles, m.p. 97°-98°.

The following additional products are obtained by the procedure ofExample 3 by substituting for the sodium ethylate the sodium salt of theR₂ XH compound shown in the first column and, if desired, substitutingan R₃ -substituted nitrophenylhydrazine for the 2nitrophenylhydrazine inExample 1, part a. The free acids and salts (R₁ = H or Na or K) areobtained as in Example 3, parts b and c, respectively.

    __________________________________________________________________________     ##STR10##                                                                    Example                                                                             R.sub.2 XH       R.sub.1                                                                           R.sub.2 X        R.sub.3                           __________________________________________________________________________     7    C.sub.2 H.sub.5 OH                                                                             CH.sub.3                                                                          C.sub.2 H.sub.5 O                                                                              H                                  8    C.sub.2 H.sub.5 OH                                                                             H   C.sub.2 H.sub.5 O                                                                              7-Cl                               9    C.sub.4 H.sub.9 OH                                                                             C.sub.2 H.sub.5                                                                   C.sub.4 H.sub.9 O                                                                              8-CH.sub.3                        10                                                                                   ##STR11##       C.sub.2 H.sub.5                                                                    ##STR12##       8-Br                              11                                                                                   ##STR13##       C.sub.2 H.sub.5                                                                    ##STR14##       H                                 12    (CH.sub. 3).sub.2 NCH.sub.2 CH.sub.2 OH                                                        C.sub.3 H.sub.7                                                                   (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2 O                                                          6-Br                              13    NH.sub.2 CH.sub.2 CH.sub.2 OH                                                                  C.sub.2 H.sub.5                                                                   NH.sub.2 CH.sub.2 CH.sub.2 O                                                                   8-CH.sub.3                        14                                                                                   ##STR15##       C.sub.2 H.sub.5                                                                    ##STR16##       H                                 15                                                                                   ##STR17##       CH.sub.3                                                                           ##STR18##       H                                 16                                                                                   ##STR19##       C.sub.2 H.sub.5                                                                    ##STR20##       H                                 17                                                                                   ##STR21##       C.sub.2 H.sub.5                                                                    ##STR22##       H                                 18                                                                                   ##STR23##       Na                                                                                 ##STR24##       9-Cl                              19                                                                                   ##STR25##       C.sub.4 H.sub.9                                                                    ##STR26##       H                                 20                                                                                   ##STR27##       C.sub.2 H.sub.5                                                                    ##STR28##       H                                 21    C.sub.4 H.sub.9 SH                                                                             C.sub.2 H.sub.5                                                                   C.sub.4 H.sub.9 S                                                                              H                                 22    C.sub.3 H.sub.7 SH                                                                             CH.sub.3                                                                          C.sub.3 H.sub.7 S                                                                              7-Cl                              23    C.sub.2 H.sub.5 SH                                                                             C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5 S                                                                              8-CH.sub.3                        24                                                                                   ##STR29##       C.sub.2 H.sub.5                                                                    ##STR30##       H                                 25    (CH.sub.3).sub.2 CHOH                                                                          H   (CH.sub.3).sub. 2 CHO                                                                          H                                 26                                                                                   ##STR31##       H                                                                                  ##STR32##       8-OCH.sub.3                       27    (CH.sub.3).sub.2 NCH.sub.2 CHOH                                                                C.sub.2 H.sub.5                                                                   (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2O                                                           8-OC.sub.2 H.sub.5                28    (C.sub.4 H.sub.9).sub.2 NCH.sub.2 CH.sub.2 OH                                                  H   (C.sub.4 H.sub.9).sub.2 NCH.sub.2 CH.sub.2                                                     H                                 29                                                                                   ##STR33##       H                                                                                  ##STR34##       H                                 __________________________________________________________________________

what is claimed is:
 1. A compound of the formula ##STR35## wherein R₁ ishydrogen or lower alkyl;R₂ is hydrogen, lower alkyl, phenyl-loweralkylene or ##STR36## wherein R₄ and R₅ each is hydrogen or lower alkylor together with the nitrogen complete one of the heterocyclicspyrrolidion, piperidino, said heterocyclics being unsubstituted orsubstituted with one or two lower alkyl groups; R₃ is hydrogen, loweralkyl, halogen or lower alkoxy; X is oxygen or sulfur;and salts thereof.2. A compound as in claim 1 wherein X is oxygen.
 3. A compound as inclaim 1 wherein X is sulfur.
 4. A compound as in claim 1 wherein R₁ andR₂ each is hydrogen or lower alkyl; R₃ is hydrogen and X is sulfur oroxygen.
 5. A compound as in claim 1 wherein R₁ is lower alkyl; R₂ ishydrogen or lower alkyl; R₃ is hydrogen and X is oxygen or sulfur.
 6. Acompound as in claim 1 wherein R₂ --X is di-lower alkylamino-loweralkoxy.
 7. A compound as in claim 1 wherein R₃ is hydrogen.
 8. Acompound as in claim 7 wherein R₁ is ethyl and R₂ --X is hydroxy.
 9. Acompound as in claim 7 wherein R₁ is ethyl and R₂ --X is mercapto.
 10. Acompound as in claim 7 wherein R₁ is ethyl and R₂ --X is ethoxy.
 11. Acompound as in claim 7 wherein R₁ is ethyl and R₂ --X isdimethylaminopropoxy.
 12. A compound as in claim 7 wherein R₁ is ethyland R₂ --X is methylthio.